Myocardial ischemia and infarction are associated with excessive norepinephrine (NE) release from sympathetic nerve endings (See reference 1). Cardiac dysfunctions, such as arrhythmias ensue, resulting in high morbidity and mortality. (References 2, 3). In these pathological conditions, NE is released principally by a reversal of the normal NE re-uptake pathway (NE transporter) in cardiac sympathetic nerves. This is known as “carrier mediated” release of NE in contrast to the normal exocytotic release of NE. Several lines of evidence suggest that changes in intracellular sodium (Nai) influence this pathological NE release.
The anoxia resulting from myocardial ischemia perturbs the metabolism of the neuron and is characterized by intracellular acidosis, depletion of ATP stores, and accumulation of free NE in the axoplasm. A consequence of this pathological state is compromised function of the Na+ pump (Na+/K+ ATPase), which leads to accumulation of Nai. In addition, the intracellular acidosis activates the Na+/H+ exchanger (NHE) whose function is dependent on intracellular pH. NHE extrudes intracellular H+ in exchange for extracellular Na+. NHE activation exacerbates the accumulation of Nai and thereby favors the release of free NE via the NE transporter (“carrier mediated” NE release).
Histamine H3 receptors (H3R, reference 7) were recently discovered to be present in cardiac sympathetic nerve endings. (References 8-10). To date, however, there has been no direct link between stimulation of histamine H3 receptors and inhibition of Na+/H+ exchanger activity or any other mechanism capable of regulating Na+ ion transfer in sympathetic nerve endings (SNEs). These mechanisms include the action of Na+/K+ ATPase, the voltage-dependent Na+ channel, the Na+/Ca++ exchanger, the Na+/K+ exchanger and any plasma membrane protein that can mediate a change in the intracellular Na+ concentration in SNEs.
Furthermore, in addition to the mechanisms that may be involved in increasing Nai, any mechanism that may be involved in modulating H+i, such as one involving H+i/ATPase, or a mechanism involved in modulating Cai, e.g. modulation of the L-Ca2+ channel, may play a major role in producing conditions that favor the pathological carrier mediated release of NE under ischemic conditions.
In the absence of direct evidence implicating a particular mechanism, there is no reasonable likelihood that stimulation of histamine H3 receptors will decrease norepinephrine release associated with a pathological condition, such as myocardial ischemia in humans. Similarly, absent such direct evidence, there is no reasonable likelihood that such decrease in norepinephrine release will successfully treat cardiac dysfunctions resulting from excessive norepinephrine (NE) release under these conditions.
Moreover, in the rat, an animal model for the intact human, it has been shown that an H3 receptor agonist failed to modulate release of NE associated with a pathological condition, such as ischemia-reperfusion. See reference 23, which is entitled “Histamine H3-receptor stimulation is unable to modulate noradrenaline (NE) release by the isolated rat heart during ischemia-reperfusion.”
There is an urgent need for methods and pharmaceutical compositions that are capable of reducing cardiac dysfunctions, such as those cardiac dysfunctions that are associated with ischemia that may result in cardiac infarctions in a human.